Chronic Lymphocytic Leukaemia (CLL)

Chronic Lymphocytic Leukaemia (CLL)

Leukaemia is a cancer of the white blood cells. There are different types of leukaemias and these are classified based on the type of white blood cells that transform into a leukaemia and also whether the cancer grows quickly(acute) or slowly(chronic).

Chronic lymphocytic leukaemia (CLL) is type of leukaemia that develops when a section of the white blood cells called lymphocytes grow without control. These cells are made in the bone marrow and travel into the blood stream. Abnormal lymphocytes are also found in the lymph nodes and spleen apart from blood and bone marrow. The function of the lymphocytes is to protect against infections. The abnormal lymphocytes present in CLL do not function properly and can also lead to a reduction in other blood cells such as red blood cells and platelets. CLL generally grows and progresses slowly.

SLL (Small lymphocytic Lymphoma)

SLL is very similar to CLL in that it develops from lymphocytes. It is a low grade lymphoma. The difference between the two is that CLL is mainly in the blood stream and SLL is more in the lymph nodes. CLL and SLL are managed in a similar way.

Chronic lymphocytic leukaemia grows slowly and most times it is diagnosed when tests are done for other reasons. A routine blood tests shows increased number of lymphocytes. Some patients develop symptoms before a diagnosis is made. These are

Enlargement of Lymph nodes

Enlargement of lymph nodes is a common symptom of CLL. These lymph nodes can be in the neck, arm pits, chest, groins or abdomen. The enlarged lymph nodes can be of varying sizes, can increase and decrease in size over time and usually not painful.


In patients with CLL there are increased number of lymphocytes which are dysfunctional and therefore patients can be more prone to develop infections which can be of any type.

Other symptoms

Other symptoms associated with CLL include weight loss, fevers, tiredness and sweating at night which can be quite significant. Easy bruising, bleeding or pains in the bones due to disease in the bone marrow can also be present.

When CLL is suspected, the following tests are done to confirm the diagnosis.

Blood Tests

A CBP or complete blood picture is a blood test done to look for increased lymphocytes in the blood which is a feature of CLL. This test can be done routinely for other reasons and CLL could bee seen on that before a diagnosis is made. In patients with SLL, which is a variant of CLL, the lymphocyte count may be normal. The CBP may also show reduced number of red blood cells and platelets.

Flow Cytometry

This is a process where blood cells are further characterised based on their physical and chemical properties. A flow cytometer is a machine which analyses the blood sample. This helps in making a diagnosis of Chronic lymphocytic leukaemia.

Bone marrow biopsy

This test is not commonly done to make a diagnosis of CLL.

Lymph node Biopsy

This test is sometimes done when enlarged lymph nodes are seen in the patient and a diagnosis of CLL is not made yet. Lymph nodes enlarge due to many reasons and a biopsy of an enlarged lymph gland may make a diagnosis of CLL or SLL.

Chest x-ray, ultrasound scan and CT scans

A chest x-ray and ultrasound scan of the abdomen is done to look for enlarged nodes or organs. A CT scan can be done for the same purpose to get a full stage of the CLL.

Genetic Tests

Genetic tests are done on the blood cells taken for tests to look for mutations that diagnose the CLL and inform the doctor about which treatment is going to be most effective. These tests are done by a method called FISH (Fluoroscence in situ hybridisation)

Chronic lymphocytic leukaemia is staged based on two systems. One is the Rai system and the other is the Binet system. Listed below is staging according to the Rai system.

Risk Stage Description
Low Risk 0 Increased lymphocytes in blood and bone marrow
Intermediate 1 Increased lymphocytes and enlarged lymph nodes
Intermediate 2 Increased lymphocytes and enlarged liver or Spleen with or without enlarged lymph nodes
High 3 Increased lymphocytes and anaemia with or Without enlarged liver, spleen or lymph nodes
High 4 Increased lymphocytes and reduced platelets With or without above factors

The Binet staging system is not listed here.

CLL has a wide spectrum of symptoms and clinical manifestations in patients. Treatment options depend on the stage of the disease at diagnosis, the age and fitness of the patient.

Early stage disease

Patients with early stage disease who do not have any symptoms are not offered any immediate treatment. They are put on close supervision with blood tests every 3 months or so and treatment is only commenced when the patient shows symptoms or there is CLL increasing faster than expected. Patients with early stage CLL may be closely monitored for years before they need to start any treatment.

Treatment in Active Disease

Patients diagnosed with CLL are termed to have active disease when they have stage 3 and 4 disease according to Rai staging system. Also, if they have anaemia or low platelet count below certain levels or have significant enlargement of lymph nodes or organs such as spleen or with symptoms such as tiredness, fever, weight loss more than 10% or sweating at night.

Treatment Options

For those patients that are considered to have active disease and need treatment, the following options are available. Treatment options may be selected based on the mutations that are found on genetic testing.


Chemotherapy is a very common option of treatment used to treat Chronic lymphocytic leukaemia. Chemotherapy is effective in controlling the cancer well and patients can have long periods of intervals in between different lines of chemotherapy. Common chemotherapy drugs or regimens used in this setting include Fludarabine, Bendamustine, Cyclofosfamide, Chlorambucil and Pentostatin. These can be given as single agents or in combination of two or more drugs or in combination with targeted therapy drugs.

Targeted therapy drugs

These are drugs that act specifically on certain targets of the CLL cells, thus being effective. They are different to chemotherapy in that they have an effect mainly on the cancer cells with less effects on normal cells as compared to chemotherapy drugs. Common types of drugs that are used as targeted agents include monoclonal antibodies and tyrosine kinase inhibitors. Drugs such as Rituximab, Ofatumumab, Alemtuzumab and Ibrutinib are commonly used to treat CLL. They are given in combination with chemotherapy and all these drugs are given into the vein. Other drugs that are used in CLL after initial therapy with drugs described above are Idelalisib, Duvelisib and Venetoclax.

Haematopoietic cell transplantation or stem cell transplantation

This is an option of treatment for some patients with CLL particularly those that are young. It is the only potential curative option of treatment in this condition.

Factors that are considered before selecting a patient for stem cell transplant include age of the patient, the presence of other medical illnesses and the fitness of the patient.

For this transplant, a donor is required from whom the stem cells are taken. This donor could be an identical twin if present, a relative like a parent or sibling (brother or sister) or a donor who is not related to the patient.

There is also assessment about how well the donor’s cells match the patient’s (HLA match). This could be a full match where there is full match in the HLA between the donor and the patient, mismatch where there is no match and haploidentical where there is a half match between the donor and the patient.
The stem cells are collected from the blood, bone marrow or cord blood if one is available.

Conditioning Treatment

Prior to having a stem cell transplant in chronic lymphocytic leukaemia, conditioning chemotherapy is given to ablate all the blood cells in the blood and marrow. This is to help kill off all the leukaemia cells prior to giving cells from the donor. Usually in CLL, a reduced intensity transplant is done as compared to patients with other conditions.

Collection of Stem Cells

Stem cells are a type of blood cells that have the capacity to develop into any kind of blood cell such as red blood, white blood cell or platelets. These stem cells are present in the blood stream and bone marrow and are initially collected from the patient before the patient receives high dose chemotherapy.
If the stem cells are from another person(donor), then it is called an Allogenic stem cell transplant. The donor can be related, usually a brother or a sister, or unrelated but matched donor. An unmatched or partially matched donor can also be used.

Before collection of stem cells, the patient may have chemotherapy and injections with G-CSF which will increase the number of stem cells in the blood to achieve a successful collection.

On the day of collection of stem cells, the donor is connected to a machine and the blood is taken out from one vein and it passes through the machine to collect the stem cells present in the blood. The blood then passes back into the donor through another vein. This process is done over a few hours.

Once the stem cells are collected, the patient receives the high dose chemotherapy. After the chemotherapy, the stem cells from the donor are infused into the patient. These cells go into the bone marrow and start making blood cells again.

Collection of bone marrow

Bone marrow is the spongy material that is present inside the bones. For a bone marrow transplant, the marrow needs to be collected prior to giving high dose chemotherapy. The procedure to collect the marrow is done under general anaesthesia usually in an operation theatre. The marrow may be taken out from different places in the bones and about 1 litre of it may be taken out at the procedure. Once taken out, it is stored and infused into the patient when needed.

Risks and side effects of Stem cell and Bone marrow Transplant

Having a stem cell or bone marrow transplant is a complex process and is associated with side effects. This procedure usually involves staying in hospital for a few weeks for the blood cells in the marrow and blood to recover to normal levels after the transplant is done. Common side effects associated with this procedure include

Nausea, Vomiting, Hair loss, altered function of the liver are potential side effects of this treatment.

Risk of Infection as white blood cells are low and the patient to prone to get an infection. The infections could be bacterial, viral or fungal and will usually need antibiotics to control them.

Mucositis is due to effect of chemotherapy on the inside lining of the mouth and digestive tract. This can limit the amount of food taken by the patient and other methods of feeding may be used in that instance.

Bleeding is a risk associated with this procedure due to low platelet count, but platelet transfusion can be given to keep the platelet counts up.
Graft versus host disease This is a reaction of the body to the transfused cells from a donor.


Radiotherapy is used as an option of treatment for some patients with CLL or SLL (small lymphocytic lymphoma) which is a variant of CLL. Radiotherapy is used in patients who have an isolated presence of disease in the form of enlarged lymph nodes in one area of the body. Radiotherapy is used to control the disease in that area. Treatment is given daily for up to 3 weeks. Radiotherapy is also used for patients with advanced disease where enlarged lymph nodes or an enlarged spleen causes symptoms to the patients.